This proposal seeks to establish the Vanderbilt University Tumor Microenvironment Network (VUTMEN) to[unreadable] contribute to the generation of a comprehensive understanding of the role of the tumor stroma in cancer[unreadable] initiation, progression, and metastasis. The strategy used by the VUTMEN is to focus our efforts on[unreadable] understanding the downstream mechanisms used by a critical biological mediator of host:tumor[unreadable] interactions.TGFbeta. Project 1 uses sophisticated mouse genetics and advanced proteomic technologies to[unreadable] identify the downstream effectors of tumor and stromal TGF|3 signaling pathways that influence mammary[unreadable] gland tumorigenesis. Project 2 uses a combination of human prostate cancer and mouse model-derived[unreadable] cells and the tissue recombination model to examine the effectors of TGFp that modulate prostatic[unreadable] carcinogenesis. The role of TGFbeta in driving the vicious cycle that regulates the growth of breast metastases[unreadable] in bone is the topic of Project 3. All results will be followed up in human tumor samples. The VUTMEN[unreadable] supports 3 "Integrative Shared Resources" that bring state-of-the-art technologies and a systems biology[unreadable] approach to the three VUTMEN projects. The Protein Collection and Proteomics Core provides proteomic[unreadable] technologies specifically relevant to the tumor microenvironment, including microdialysis and imaging mass[unreadable] spectroscopy. The Image Fusion Core is devoted to novel imaging strategies that enhance the[unreadable] understanding of the tumor microenvironment, including a multi-parametric and multi-modality approach[unreadable] known as image fusion. The Biomathematics and Bioinformatics Core develops new approaches to[unreadable] analyzing complex data sets and generates mathematical models for iterative hypothesis generation and[unreadable] testing. We propose that the acknowledged complexity of the tumor microenvironment can be unraveled by[unreadable] the strategy of focusing our efforts on the key regulatory pathway of TGFbeta. This will be achieved through the[unreadable] systematic examination of known molecular modulators that are downstream of TGFbeta and the discovery of[unreadable] new ones using proteomic approaches, examining biological effects in vivo in real time and correlating the[unreadable] results with molecular parameters using genetic manipulation and image fusion technologies, using[unreadable] mathematical modeling to iteratively generate hypotheses and test them experimentally, and comparing the[unreadable] results in three distinct but related organ sites. Our goal is to generate a comprehensive understanding of[unreadable] the mechanisms used by TGFbeta to control the reciprocal interactions between a tumor and its[unreadable] microenvironment.[unreadable] [unreadable] [unreadable]